Regulatory T Cell Development in the Thymus David L. Owen, Louisa E. Sjaastad and Michael A. Farrar This information is current as J Immunol 2019; 203:2031-2041; ; of September 27, 2021. doi: 10.4049/jimmunol.1900662 http://www.jimmunol.org/content/203/8/2031 Downloaded from References This article cites 186 articles, 68 of which you can access for free at: http://www.jimmunol.org/content/203/8/2031.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 27, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2019 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Regulatory T Cell Development in the Thymus David L. Owen, Louisa E. Sjaastad, and Michael A. Farrar ∼ Development of a comprehensive regulatory T (Treg) small population, 1% of developing CD4 single-positive cell compartment in the thymus is required to maintain thymocytes and ∼10–15% of CD4+ T cells in secondary immune homeostasis and prevent autoimmunity. In this lymphoid organs, is responsible for maintaining immune ho- study, we review cellular and molecular determinants of meostasis and is crucial for survival (4–9). Treg cells are an incredibly diverse population with regard to both TCR reper- Treg cell development in the thymus. We focus on the toire and function. T cells regulate numerous physiologic evidence for a self-antigen–focused Treg cell repertoire as reg well as the APCs responsible for presenting self-antigens processes, including maternal–fetal conflict (10–17), germ cell to developing thymocytes. We also cover the contribution tolerance (18), stem cell differentiation in the skin (19), muscle repair (20), adipocyte homeostasis and function (21–25), and of different cytokines to thymic Treg development and Downloaded from the cellular populations that produce these cytokines. retinal inflammation (26). In addition, Treg cells also regulate Finally, we update the originally proposed “two-step” effector immune responses in disease states, such as germinal center reactions (27, 28), inhibit overzealous T cell responses model of thymic T differentiation by incorporating reg during infection (29–34), enhance effector T cell differentiation new evidence demonstrating that Treg cells develop from and memory formation to pathogens (35–37), inhibit tumor two Treg progenitor populations and discuss the func- immunity (38, 39), and promote tolerance to environmental tional importance of Treg cells generated via either pro- and commensal Ags (40–42). The burden of regulating these http://www.jimmunol.org/ genitor pathway. The Journal of Immunology,2019, diverse processes has led the field to propose two broad func- 203: 2031–2041. tional classes of Treg cells, defined by their ontogeny: peripheral- derived Treg (pTreg) and thymic-derived Treg (tTreg)cells.Inthis daptive immunity evolved as a powerful defense review we focus on tTreg cell development. mechanism to eliminate foreign pathogens and A eradicate transformed cells. This system relies on two Why the thymus? chief capabilities: extensive repertoire diversity and the ability The thymus has been an organ of immense curiosity for to discriminate “self” versus “nonself” (1). In T cells, diversity immunologists for some time. Although initial thymectomy by guest on September 27, 2021 is derived from random rearrangements of the TCRa and experiments failed to reveal immunological consequences (43), TCRb loci (2, 3). However, diversity comes at a cost, as some subsequent work revealed a central function in immune re- of these rearrangements will generate self-reactive T cells ca- sponses (44–46). Work as early as 1962 by Jacques Miller pable of initiating pathogenic immune responses. The thymus suggested a role in immune tolerance, as day 3–thymectomized acts as a training ground for T cells and plays a role in en- (d3Tx) mice succumbed to an autoimmune wasting disease by suring a diverse, nonself-focused TCR repertoire capable of 3 months of age (47). A seminal study in 1969 described that eliminating pathogens. The process of generating a diverse d3Tx mice but not day 7 or later- thymectomized mice de- TCR repertoire also leads to the development of many autore- veloped autoimmunity of the ovary that could be rescued by a active T cells. Many of these autoreactive T cells are eliminated thymus transplant (48). Work by Gershon, Kondo, and col- via clonal deletion in the thymus. However, self-reactive T cells leagues (49–51) subsequently showed that thymocytes could do escape clonal deletion and, when left uncontrolled, elicit produce dominant tolerance during immune responses to detrimental autoimmune diseases. Although several mechanisms sheep RBCs and coined the term “suppressor T cells.” To- evolved to control autoimmune responses, a specialized subset of gether, these works suggested the existence of a population of + suppressor CD4 T cells, termed regulatory T (Treg) cells, plays a thymus-derived suppressive T cells that had delayed kinetics particularly important role in maintaining immune homeostasis. of thymic export. Over the past 20 years tremendous progress has been made in Although the concept of immune suppression was clearly cor- the identification and understanding of Treg cells. This relatively rect, early models for explaining this process proved unsatisfactory. Center for Immunology, University of Minnesota, Minneapolis, MN 55455; Masonic Wallin Medical Biosciences Building, Minneapolis, MN 55455. E-mail address: Cancer Center, University of Minnesota, Minneapolis, MN 55455; and Department of [email protected] Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455 Abbreviations used in this article: AIRE, autoimmune regulator; DC, dendritic cell; ORCIDs: 0000-0002-1099-0605 (D.L.O.); 0000-0003-1603-5905 (L.E.S.); 0000- d3Tx, day 3–thymectomized; MHC-II, MHC class II; mTEC, medullary thymic epi- 0002-5569-0366 (M.A.F.). thelial cell; pDC, plasmacytoid DC; pTreg, peripheral-derived Treg;Tconv, conventional T cell; TNFRSF, TNFR superfamily; T , regulatory T; T P, T cell progenitor; TSA, Received for publication June 13, 2019. Accepted for publication August 23, 2019. reg reg reg tissue-specific Ag; tTreg; thymic-derived Treg; WT, wild-type. D.L.O. and L.E.S. were supported by National Institutes of Health (NIH) T32 Training Grant 2T32AI007313. M.A.F. was supported by NIH Grant AI124512. Copyright Ó 2019 by The American Association of Immunologists, Inc. 0022-1767/19/$37.50 Address correspondence and reprint requests to Dr. Michael A. Farrar, Center for Immunology, University of Minnesota, 2101 6th Street SE, 2-116 Winston and Maxine www.jimmunol.org/cgi/doi/10.4049/jimmunol.1900662 2032 BRIEF REVIEWS: THYMIC REGULATORY T CELL DEVELOPMENT Most notably, it was suggested that suppressor T cells could increased the Treg cell proportion but not numbers in the function via a soluble factor encoded in the MHC locus I-J thymus, suggesting that engagement of cognate self-antigen (52). However, the I-J locus was eventually found not to was not driving Treg cell development (67). Nevertheless, encode a unique protein (53). This led many to reject the other studies have provided evidence that the Treg cell TCR concept of a unique population of T cells capable of immune repertoire is more self-reactive than its conventional coun- suppression (54). Despite these controversies, work in the terpart and that acquisition of agonist TCR stimulation is early 1980s already suggested the presence of a subpopulation important in Treg cell development. This view originated from of T cells, defined by anti–Lyt-1 (later described as CD5) Ab early experiments observing the presence of CD25+ cells in positivity, that were capable of suppressing autoimmunity in the thymus of wild-type (WT) mice but not those expressing a d3Tx mice (55). A seminal study by Sakaguchi et al. (4) transgenic TCR specific for foreign Ag (68). This hypothesis in 1995 discovered that CD25+ T cells were necessary and was confirmed in later studies showing that TCR transgenics sufficient for suppressing autoimmune responses. The iden- could drive thymic Treg cell development only when the tification of CD25 as a marker of suppressive T cells was cognate Ag was also expressed in the thymus (69). Further, critical to add legitimacy to the field (4). A follow-up study TCR sequencing experiments on mice with reduced TCR connected this concept to autoimmunity observed in d3Tx repertoires observed that Treg TCRs are largely distinct from + experiments, as d3Tx prevented accumulation of CD25 cells Tconv TCRs (70, 71), but overlap with TCRs expressed by 2 2 in the periphery of mice. Transfer of CD25+ cells into d3Tx pathogenic self-reactive T cells in Foxp3 / mice (72). In ad- mice was able to rescue autoimmunity, whereas transfer of dition, a series of experiments observed that intraclonal com- Downloaded from CD25-depleted splenocytes caused autoimmunity in athymic petition for cognate Ag limits Treg cell differentiation (73, 74), mice, revealing that thymically derived CD25+ T cells were suggesting that interaction with Ag, presumably self-antigen, is critical controllers of autoimmunity (56). Groundbreaking important for Treg cell development. Later work used TCR studies in humans suffering from immune dysregulation, transgenics with various affinity for OVA and observed a polyendocrinopathy, enteropathy, X-linked syndrome, and in linear relationship between TCR affinity and Treg cell devel- scurfy mice identified a critical role for the transcription factor opment (75).